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Science 332 (6028): 484-488

Copyright © 2011 by the American Association for the Advancement of Science

Proteoglycan-Specific Molecular Switch for RPTP{sigma} Clustering and Neuronal Extension

Charlotte H. Coles,1,* Yingjie Shen,2,* Alan P. Tenney,2,3,{dagger} Christian Siebold,1,{dagger} Geoffrey C. Sutton,1 Weixian Lu,1 John T. Gallagher,4,5 E. Yvonne Jones,1,{ddagger} John G. Flanagan,2,{ddagger} A. Radu Aricescu1,{ddagger}

Abstract: Heparan and chondroitin sulfate proteoglycans (HSPGs and CSPGs, respectively) regulate numerous cell surface signaling events, with typically opposite effects on cell function. CSPGs inhibit nerve regeneration through receptor protein tyrosine phosphatase sigma (RPTP{sigma}). Here we report that RPTP{sigma} acts bimodally in sensory neuron extension, mediating CSPG inhibition and HSPG growth promotion. Crystallographic analyses of a shared HSPG-CSPG binding site reveal a conformational plasticity that can accommodate diverse glycosaminoglycans with comparable affinities. Heparan sulfate and analogs induced RPTP{sigma} ectodomain oligomerization in solution, which was inhibited by chondroitin sulfate. RPTP{sigma} and HSPGs colocalize in puncta on sensory neurons in culture, whereas CSPGs occupy the extracellular matrix. These results lead to a model where proteoglycans can exert opposing effects on neuronal extension by competing to control the oligomerization of a common receptor.

1 Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK.
2 Department of Cell Biology and Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA.
3 Motor Neuron Center, Columbia University, New York, NY 10032, USA.
4 School of Cancer and Imaging Sciences, Faculty of Medical and Health Sciences, University of Manchester, Paterson Institute for Cancer Research, Manchester M20 4BX, UK.
5 Iduron, Paterson Institute for Cancer Research, University of Manchester, Manchester M20 4BX, UK.

* These authors contributed equally to this work.

{dagger} These authors contributed equally to this work.

{ddagger} To whom correspondence should be addressed. E-mail: radu{at}strubi.ox.ac.uk (A.R.A.); flanagan{at}hms.harvard.edu (J.G.F.); yvonne{at}strubi.ox.ac.uk (E.Y.J.)


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